Bone density and fracture risk following SBRT for non-spine bone metastases

Purpose/methods This retrospective study evaluated local recurrence (LR) and fracture risk in non-spine bone metastases treated with SBRT. Results 181 lesions in 116 patients are reported. The median dose was 27 Gy (range 15-40) in 3 fractions (range 1-6). The cumulative incidence of LR was 2.8%, 7.2% and 12.5% at 6 mo, 1 yr and 2 yrs. Fractures occurred in 11 lesions (6%). Radioresistant histology and increasing PTV predicted for LR on univariate analysis, while rib location was associated with control. Increasing PTV remained a significant predictor for LR on multivariate analysis. Univariate predictors of fracture risk included female gender, lytic lesions and poorer KPS. Average CT-approximated L1 trabecular attenuation in patients with fracture was significantly lower than in patients without fracture (112.2 vs. 142.6 Hounsfield units). Conclusion In the largest series to date, we report excellent local control for SBRT to non-spine bone metastases and a novel relationship between CT-based bone quality assessment and fracture risk.


INTRODUCTION
Modern systemic treatments such as targeted therapy and immunotherapy have greatly changed the landscape of cancer care and altered the course of metastatic disease. As such, more cancer patients are surviving in a metastatic state [1], particularly those with histologies like breast and prostate cancer [2]. The prevalence of women living in the United States with metastatic breast cancer, for instance, is estimated to have increased by 4% from 1990 to 2000, 17% from 2000 to 2010, and by a projected 31% from 2010 to 2020. Moreover, approximately one third of patients with metastatic breast cancer now live for five years or more with a stage IV diagnosis [3].
Bone metastases are a common source of morbidity in patients with advanced cancer, causing pain as well as increased fracture risk necessitating surgical stabilization. Conventional radiation therapy (RT) has long been a mainstay of treatment for symptomatic osseous metastases, and its ability to provide rapid and clinically significant palliation of pain has been consistently supported in the literature. Common treatment regimens such as 30 Gy in 10 fractions, 20 Gy in 5 fractions, and 8 Gy in 1 fraction have been shown to confer equivalent initial palliative efficacy, providing pain reduction in 60-70% of patients [4][5][6]. However, pain relapse occurs in as many as half of initial responders within one year after treatment and up to 40% of patients require reirradiation [7]. Moreover, durable local control is often not achieved with these regimens.
Given these limitations, there has been increasing interest in using advanced radiation therapy techniques such as stereotactic body radiation therapy (SBRT) to deliver higher biologically effective dose (BED) to bone metastases than can be offered with conventional RT regimens. SBRT may therefore be able to provide more durable local control and pain relief in patients with symptomatic metastases. While SBRT has been increasingly explored in the treatment of spine metastases with promising local control rates, ranging from 70% to greater than 90% at 1-2 years [8][9][10], the literature for local control and toxicity rates in non-spine bone metastases treated with SBRT remains sparse. We present the largest series of SBRT to non-spine bone metastases published to date and perform a novel analysis of the relationship between CT-based bone quality assessment and the risk of radiation-induced fracture.

MATERIALS AND METHODS
A retrospective review was conducted of patients treated with SBRT to at least one non-spine bone lesion of any primary histology between the years of 2010 and 2018. Patients were excluded if they did not have at least one follow up visit subsequent to SBRT. Previous irradiation to the site of SBRT was allowed. Data collected included patient and disease characteristics (i.e. gender, age at treatment, performance status, tumor location and size, lytic or sclerotic nature of lesion), treatment characteristics (i.e. radiation therapy prescription and dates, planning tumor volume expansion margin, and planning target volume), and follow-up information (i.e. date of fracture adverse event, date of death and/ or last follow-up, and date of local recurrence). Patients were categorized as oligometastatic if they had five or fewer metastases. Radioresistant histologies were defined per Laufer et al. as renal cell carcinoma, nonsmall cell lung cancer, sarcoma, thyroid, hepatocellu-lar carcinoma, and colorectal carcinoma [11]. Ewing sarcoma was categorized as a radiosensitive histology within the sarcoma family [12]. Fracture events were recorded according to the date of first radiographic diagnosis. If accidental falls or other trauma caused fractures in areas clearly unrelated to the SBRT site (i.e. different part of the body), these were not recorded as a radiation-related event.
For bone quality assessment, a previously described CT-based method to approximate bone density using trabecular attenuation in the first lumbar vertebra was utilized [13]. For each CT, an ovoid region of interest was delineated on an axial slice of L1 between the superior end plate and the midline zone, and the average Hounsfield units (HU) within this region was recorded. The closest qualifying CT scan to the start of SBRT was used and was considered eligible if it was obtained within 12 months of SBRT, was performed at 120 kV, and showed no evidence of diffuse lumbar metastatic disease or other abnormality prohibiting representative density measurement (e.g. spinal hardware artifact or compression deformity). Diagnostic CT or PET/CT and simulation CT were all allowable if the above criteria were met.
Prescription doses for SBRT treatments ranged from 15-40 Gy in 1-6 fractions. BED calculations were performed using the equation where D is the total dose in Gy, d is the dose per fraction, and the α/β is estimated to be 10 for all tumors. Gross tumor volume (GTV) was defined as the gross visible lesion on diagnostic PET/CT, CT or MRI imaging. An expansion margin at the treating radiation oncologist's discretion was applied to the GTV to create a clinical target volume (CTV). The CTV was then expanded by a margin of 2-10mm to account for variability in daily treatment setup to create a planning target volume (PTV). Treatment was delivered using a linear accelerator-based machine with daily pre-treatment cone-beam CT image guidance. Local control was evaluated retrospectively for each treated bone lesion using follow-up notes, radiology reports, and imaging review to assess for local recurrence. Local recurrence was defined per the MD Anderson criteria as greater than 25% measurable or subjective increase in size of target lesion [14]. Each local recurrence was independently reviewed by two radiation oncologists for confirmation.
The cumulative incidence of local recurrence and fracture were estimated using competing risks analysis. Bivariate and multivariate relationships between clinical and treatment factors with both local recurrence and fracture toxicity were analyzed with Fine-Gray competing risks regression to report subdistribution hazard ratio estimates. Clinically meaningful variables or variables with p<0.05 on univariate analysis were included in multivariate analysis. Bone quality analysis (L1 trabecular attenuation) between patients who fractured at the site of SBRT and patients who did not have evidence of fracture was conducted with a one-tailed student T-test.

Local Control Outcomes
Median follow up was 18.6 months (range 1.6-60. 8  time to failure of 9.9 months (range 1.4-41.1). The cumulative incidence of local recurrence at 6 months, 1 year, and 2 years was 2.8%, 7.2%, and 12.5%, respectively ( Figure 1). The univariate and multivariate analyses are summarized in Table 3 a) and b), respectively. On univariate analysis, radioresistant histology was predictive of local failure (HR 2.77, p=0.0278), while rib metastases were associated with a decreased risk of local recurrence (HR 0.18, p=0.0211). Increasing size of GTV and PTV were both predictive of local recurrence as continuous variables, with each 1 cc increase in GTV conferring a 4% increased risk of local failure (p=0.0287) and each 5 cc increase in PTV conferring a 3% increased risk of local failure (p=0.0003). No significant association of BED10 with local control was observed. On multivariate analysis while accounting for BED10, increasing PTV volume remained a significant predictor of local recurrence (HR 1.02, p=0.0292), suggesting that each 5 cc increase in PTV conferred a 2% increased risk of local recurrence.

Fracture Toxicity Outcomes
Radiographic fractures were recorded in 11 out of the 181 treated sites, with a median time to fracture of 7.5 months (range 1.1-22.4). The cumulative incidence of fracture at 6 months, 1 year, and 2 years was 2.3%, 4.7% and 7.7% respectively (Figure 2). One fracture occurred following accidental trauma. Fractures occurred in 6 rib lesions, 2 scapular lesions, 2 pubic bone lesions, and 1 ilium lesion. No post-treatment fractures were recorded for lesions in the hip/ lower extremity or sacroiliac joint (i.e. traditionally weight-bearing bones). None of the three previously irradiated sites had evidence of fracture. Seven of these fractures were symptomatic, while the rest were diagnosed incidentally on surveillance/re-staging imaging alone. All of the fractures were managed conservatively and did not require surgical management. The univariate and multivariate analyses are summarized in Table 4 a) and b), respectively. On univariate analysis, female gender (HR 8.33, p=0.0006) and lytic and mixed lytic/blastic type lesions (i.e. lesions with a lytic component, HR 4.35, p=0.0211) correlated with fracture toxicity. Additionally, better performance status significantly correlated with decreased fracture risk, with each 10-point increase in KPS conferring a 62% relative decrease in risk of fracture. On multivariate analysis incorporating BED10, gender, KPS, and lesion type, none of the variables remained statistically significant.

Bone Integrity Analysis
The mean L1 trabecular attenuation value was available for 97 of 116 patients, including nine of the 11 patients who had recorded fracture. The median absolute time between start of SBRT and imaging used to obtain the L1 attenuation value was 0.95 months (range 0-8.04). The mean attenuation value for patients who fractured at the SBRT site was 112.2 HU, while this value was 142.6 HU for patients without recorded fracture (p=0.036).

DISCUSSION
SBRT for non-spine bone metastases is being increasingly utilized. A recent phase II trial of predominantly non-spine bone metastases demonstrated improved pain relief and local control with SBRT compared to conventional RT, and importantly, with comparable risk of post-treatment fracture [15]. Nonetheless, factors impacting local control and toxicity following non-spine bone SBRT remain uncertain. We present the largest report of SBRT outcomes for non-spine bone metastases as well as the longest patient follow-up in the current literature. Our local control rates of 92.8% at 1 year and 87.5% at 2 years are comparable to the outcomes reported in the two prior series that focus on SBRT in non-spine bone metastases. Specifically, Owen et al. reported a 1-year local control rate of 91.8% in 74 patients treated to 85 lesions [16], and Erler et al.

Figure 1. Cumulative incidence plot of local recurrence
Bone density and fracture risk following SBRT for non-spine bone metastases [17]. Our results are consistent with previously published data in showing an association between local recurrence and PTV volume [17]. In addition, we identified radioresistant histology as a predictor for higher risk of local recurrence, suggesting that these patients may benefit from further dose escalation beyond the common fractionation schemes such as 9-10 Gy x 3 fractions or 6 Gy x 5 fractions prescribed in our series.
Our cumulative fracture rate of 6% is consistent with the two prior studies that reported the risk as 2% and 8%, respectively [16,17]. However, our study is a unique contribution to the literature in that our larger cohort allowed for a detailed analysis of risk factors for SBRT-induced fracture. Consistent with the spine SBRT literature, univariate analysis found that lesions with a lytic component were at higher risk of fracture compared to sclerotic lesions [18][19][20]. In addition, female gender and poor performance status were associated with higher fracture risk. Because dual-energy x-ray absorptiometry (DXA) scans are rarely performed in our patient population, to further investigate the relationship between bone density and fracture risk following SBRT, we utilized CT trabecular attenuation values in the L1 vertebra to examine the relationship between baseline bone density and fracture risk.  This measure correlates well with T-scores from DXA [21,22] and is widely available for cancer patients. It is generally thought that values of less than 100 HU using this method of assessment are concerning for osteoporosis and higher fracture risk. We found that bone density estimated in this manner was significantly lower in patients who developed fractures than in those who did not. Although larger multi-institutional studies are necessary to confirm these results, this important finding may be used to distinguish patients who are appropriate candidates for SBRT alone from those that warrant prophylactic stabilization. As a retrospective study, we acknowledge several inherent biases, including patient and treatment selection. Furthermore, our analysis was limited by the low number of fracture events in our cohort. Notably, L1 attenuation values could not be obtained for two of the 11 patients who fractured, one due to diffuse metastatic disease in the lumbar spine and the other due to preexisting L1 compression fracture. In addition, while the series from Owens et al. and Erler et al. also both included a majority of patients with prostate cancer (31-32%), our series includes a greater predominance of prostate primary histology, accounting for over 60% of the patients. We recognize this as a limitation of our study that may decrease the generalizability of our findings. Moreover, our univariate analysis identified radioresistant histology as a statistically significant predictor of local recurrence, and therefore our local control rates may be somewhat inflated by a dispro-portionate representation of a radiosensitive histology. Nonetheless, this series represents an important contribution to the literature given the large cohort and mature follow-up with 78% of treated lesions followed for a least 1 year post-treatment.
In conclusion, our study demonstrates that SBRT to non-spine bone metastases results in excellent rates of local control with low risk of radiation-associated fracture. Importantly, we report a relationship between bone density -as measured by a well-validated and highly accessible CT-based tool -and risk of SBRTassociated fracture. This novel finding may serve as a foundation for future studies to identify patients who are appropriate candidates for SBRT alone from those that warrant prophylactic stabilization.